Summary of work: Type 2 diabetes is one of the most common diseases in the elderly population of the USA, and is especially common in minority populations. This hyperglycemic state is caused by 1) impaired insulin secretion from islets of Langerhans in the pancreas, and 2) impaired sensitivity of peripheral tissues (such as muscle, fat, and liver) to insulin. Our objective is to develop therapeutic strategies that may address both these problems in type 2 diabetes. A promising new approach for treatment is the use of incretin hormones such as glucagon-like peptide (GLP-1). Our work is based on our finding that GLP-1 stimulates insulin action at insulin target tissues. Our study establishes an extrapancreatic effect of GLP-1 using tissue culture models of fat and muscle. This is a difficult task to achieve in a more complex situations such as in animal studies, since a multitude of factors such as levels of blood glucose, insulin, glucagon, somatostatin and other contraregulatory hormones (such as cortisol, etc...) are affected by GLP-1 administration. Our data have shown that insulin-mediated glucose uptake and lipid synthesis in cultured adipocytes are stimulated by GLP-1 and GLP-1 stimulates glucose oxidation and glycogen synthesis in rat myotubes in culture. Our data also suggest the presence of different GLP receptor isoforms in pancreas versus extrapancreatic tissues. We have evidence that the GLP signaling cascade (G-protein coupling) is different in pancreas versus extrapancreatic tissues. Further, different ligand specificity for GLP analogs are noted in pancreas versus extrapancreatic tissues. This suggests the exciting possibility to activate selectively GLP receptor isoforms in different tissues in type 2 diabetes therapy. Our work concerning the effect of GLP-1 in 3T3-L1 adipocytes is now in press in Journal of Cell Physiology and two other manuscripts are being written describing GLP-1 effects in L6 myotubes and the different signal transduction pathways of GLP-1 receptor signaling.